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Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype


Two common serotonin transporter (SERT) untranslated region gene variants have been intensively studied, but remain inconclusively linked to depression and other neuropsychiatric disorders. We now report an uncommon coding region SERT mutation, Ile425Val, in two unrelated families with OCD and other serotonin-related disorders. Six of the seven family members with this mutation had OCD (n=5) or obsessive-compulsive personality disorder (n=1) and some also met diagnostic criteria for multiple other disorders (Asperger's syndrome, social phobia, anorexia nervosa, tic disorder and alcohol and other substance abuse/dependence). The four most clinically affected individuals—the two probands and their two slbs—had the I425V SERT gene gain-of-function mutation and were also homozygous for 5′-UTR SERT gene variant with greater transcriptional efficacy.

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  1. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS et al. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci USA 1993; 90: 2542–2546.

    CAS  Article  Google Scholar 

  2. Lesch K-P, Wolozin BL, Estler HC, Murphy DL, Riederer P . Isolation of a cDNA encoding the human brain serotonin transporter. J Neural Transm 1993; 91: 67–72.

    CAS  Article  Google Scholar 

  3. Gelernter J, Pakstis AJ, Kidd KK . Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17. Hum Genet 1995; 95: 677–680.

    CAS  Article  Google Scholar 

  4. Androutsellis-Theotokis A, Rudnick G . Accessibility and conformational coupling in serotonin transporter predicted internal domains. J Neurosci 2002; 22: 8370–8378.

    CAS  Article  Google Scholar 

  5. Murphy DL, Li Q, Engel S, Wichems C, Andrews A, Lesch KP et al. Genetic perspectives on the serotonin transporter. Brain Res Bull 2001; 56: 487–494.

    CAS  Article  Google Scholar 

  6. Lopez AD, Murray CC . The global burden of disease, 1990–2020. Nat Med 1998; 4: 1241–1243.

    CAS  Article  Google Scholar 

  7. Nestadt G, Samuels J, Riddle M, Bienvenu OJ, Liang KY, LaBuda M et al. A family study of obsessive-compulsive disorder. Arch Gen Psychiatry 2000; 57: 358–363.

    CAS  Article  Google Scholar 

  8. Bengel D, Greenberg BD, Corá-Locatelli G, Altemus M, Heils A, Li Q et al. Association of the serotonin transporter promoter regulatory region and obsessive-compulsive disorder. Mol Psychiatry 1999; 4: 463–466.

    CAS  Article  Google Scholar 

  9. McDougle CJ, Epperson CN, Price LH, Gelernter J . Evidence for linkage disequilibrium between serotonin transporter protein gene (SLC6A4) and obsessive compulsive disorder. Mol Psychiatry 1998; 3: 270–273.

    CAS  Article  Google Scholar 

  10. Cavallini MC, Di Bella D, Siliprandi F, Malchiodi F, Bellodi L . Exploratory factor analysis of obsessive-compulsive patients and association with 5-HTTLPR polymorphism. Am J Med Genet 2002; 114: 347–353.

    Article  Google Scholar 

  11. Alsobrook JP, Leckman JF, Goodman WK, Rasmussen SA, Pauls DL . Segregation analysis of obsessive-compulsive disorder using symptom-based factor scores. Am J Hum Genet 1999; 88: 669.

    Article  Google Scholar 

  12. Demchyshyn LL, Pristupa ZB, Sugamori KS, Barker EL, Blakely RD, Wolfgang WJ et al. Cloning, expression, and localization of a chloride-facilitated, cocaine-sensitive serotonin transporter from Drosophila melanogaster. Proc Natl Acad Sci USA 1994; 91: 5158–5162.

    CAS  Article  Google Scholar 

  13. Lesch K-P, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–1531.

    CAS  Article  Google Scholar 

  14. Killic F, Murphy DL, Rudnick G . A human serotonin transporter mutation causes constitutive activation of transport activity. Mol Pharmacol, in press.

  15. Glatt CE, DeYoung JA, Delgado S, Service SK, Giacomini KM, Edwards RH et al. Screening a large reference sample to identify very low frequency sequence variants: comparisons between two genes. Nat Genet 2001; 27: 435–438.

    CAS  Article  Google Scholar 

  16. Bienvenu OJ, Samuels JF, Riddle MA, Hoehn-Saric R, Liang KY, Cullen BA et al. The relationship of obsessive-compulsive disorder to possible spectrum disorders: results from a family study. Biol Psychiatry 2000; 48: 287–293.

    CAS  Article  Google Scholar 

  17. Pauls DL, Alsobrook II JP, Goodman W, Rasmussen S, Leckman JF . A family study of obsessive-compulsive disorder. Am J Psychiatry 1995; 152: 76–84.

    CAS  Article  Google Scholar 

  18. Fombonne E . What is the prevalence of Asperger disorder? J Autism Dev Disord 2001; 31: 363–364.

    CAS  Article  Google Scholar 

  19. McDougle CJ, Kresch LE, Goodman WK, Naylor ST, Volkmar FR, Cohen DJ et al. A case-controlled study of repetitive thoughts and behavior in adults with autistic disorder and obsessive-compulsive disorder. Am J Psychiatry 1995; 152: 772–777.

    CAS  Article  Google Scholar 

  20. Folstein SE, Rosen-Sheidley B . Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001; 2: 943–955.

    CAS  Article  Google Scholar 

  21. Piven J, Palmer P . Psychiatric disorder and the broad autism phenotype: evidence from a family study of multiple-incidence autism families. Am J Psychiatry 1999; 156: 557–563.

    CAS  PubMed  Google Scholar 

  22. Smalley SL, McCracken J, Tanguay P . Autism, affective disorder, and social phobia. Am J Med Genet 1995; 60: 19–26.

    CAS  Article  Google Scholar 

  23. Bolton PF, Pickles A, Murphy M, Rutter M . Autism, affective and other psychiatric disorders: patterns of familial aggregation. Psychol Med 1998; 28: 385–395.

    CAS  Article  Google Scholar 

  24. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ . The genetic epidemiology of phobias in women. The interrelationship of agoraphobia, social phobia, situational phobia, and simple phobia. Arch Gen Psychiatry 1992; 49: 273–281.

    CAS  Article  Google Scholar 

  25. Fireman B, Koran LM, Leventhal JL, Jacobson A . The prevalence of clinically recognized obsessive-compulsive disorder in a large health maintenance organization. Am J Psychiatry 2001; 158: 1904–1910.

    CAS  Article  Google Scholar 

  26. Gorwood P, Bouvard M, Mouren-Simeoni MC, Kipman A, Ades J . Genetics and anorexia nervosa: a review of candidate genes. Psychiatr Genet 1998; 8: 1–12.

    CAS  Article  Google Scholar 

  27. Altemus M, Murphy DL, Greenberg B, Lesch KP . Intact coding region of the serotonin transporter gene in obsessive-compulsive disorder. Am J Med Genet 1996; 67: 409–411.

    CAS  Article  Google Scholar 

  28. Collins FS, Brooks LD, Chakravarti A . A DNA polymorphism discovery resource for research on human genetic variation. Genome Res 1998; 8: 1229–1231.

    CAS  Article  Google Scholar 

  29. Enoch MA, Greenberg BD, Murphy DL, Goldman D . Sexually dimorphic relationship of a 5-HT2A promoter polymorphism with obsessive-compulsive disorder. Biol Psychiatry 2001; 49: 385–388.

    CAS  Article  Google Scholar 

  30. Kaye WH, Lilenfeld LR, Berrettini WH, Strober M, Devlin B, Klump KL et al. A search for susceptibility loci for anorexia nervosa: methods and sample description. Biol Psychiatry 2000; 47: 794–803.

    CAS  Article  Google Scholar 

  31. Ozaki N, Rosenthal NE, Pesonen U, Lappalainen J, Feldman-Naim S, Schwartz PJ et al. Two naturally occurring amino acid substitutions of the 5-HT2A receptor: similar prevalence in patients with seasonal affective disorder and controls. Biol Psychiatry 1996; 40: 1267–1272.

    CAS  Article  Google Scholar 

  32. Haliassos A, Chomel JC, Grandjouan S, Kruh J, Kaplan JC, Kitzis A . Detection of minority point mutations by modified PCR technique: a new approach for a sensitive diagnosis of tumor-progression markers. Nucleic Acids Res 1989; 17: 8093–8099.

    CAS  Article  Google Scholar 

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We thank our patient and family collaborators, Drs Gabriella Cora-Locatelli, Margaret Altemus, Theresa Pigott, Catherine Stayer, Joshua Rosenthal plus Diane Kazuba, Lucy Justement, Su-Jan Huang, Liz Maxwell, Julie Guroff, Teresa Tolliver and Theresa B DeGuzman for their contributions to this study, and Drs Klaus-Peter Lesch, Judith Rapoport and Sevilla Detera-Wadleigh for helpful suggestions with the manuscript. During the early stages of this work, Dr Norio Ozaki was supported at the NIAAA and NIMH Intramural Programs by Research Grants (10670923, 13470198, 13877152) from the Ministry of Science Education and Culture of Japan, the Research Grant for Nervous and Mental Disorders from the Ministry of Health and Welfare of Japan, and Special Coordination Funds for Promoting Science and Technology Target-oriented Brain Science Research Program from the Ministry of Science and Technology of Japan.

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Correspondence to D L Murphy.

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Ozaki, N., Goldman, D., Kaye, W. et al. Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol Psychiatry 8, 933–936 (2003).

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  • genetics
  • obsessive-compulsive disorder
  • autism
  • anorexia
  • constitutive activation

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